Project Summary ? Abstract Combat operations in Afghanistan and Iraq have been associated with increased prevalence of posttraumatic stress disorder (PTSD) among veterans. Recent data demonstrate that those with PTSD demonstrate higher rates of alcoholism and alcohol use disorders (AUDs). The unique effects of PTSD+AUD compared to PTSD alone make the diagnosis, management, treatment, and rehabilitation of those affected a challenge in VA, military, and civilian medical facilities. It has become increasingly important to recognize symptoms in Veterans with comorbid PTSD+AUD compared to those symptoms associated with AUD or PTSD alone, in the rehabilitation period. One mechanism to have recently come into focus to explain the compounded effects of comorbid PTSD+AUD is impaired cortical activation that leads to loss of top-down control of the striatum, a region that governs reward and habit responding in addictive disorders, such as AUD. Surprisingly, to date, there have been few preclinical studies to evaluate the impact of PTSD on neuroactivity in the striatum, adding to the significance and conceptual innovation of the proposed project. This knowledge gap will be addressed in the current application by examining striatal activation in comorbid PTSD+AUD, using a rodent model of PTSD. Striatal activation will be evaluated at numerous levels, including markers of excitatory/inhibitory neurotransmission, dendritic structure, neural activation and striatal- mediated behaviors. One mechanism common to both PTSD and AUD involves the cannabinoid system and evidence suggests that cannabinoid ligands have therapeutic potential for these disorders. The strength of this application is the comprehensive analysis of striatal function from receptor expression and activation to behavioral measures and use of novel imaging modalities to examine the longitudinal progression of brain- behavior relationships. In addition, rehabilitative interventions using novel cannabinoidergic drugs, such as methanandamide, will be employed as translationally-relevant therapies for comorbid PTSD+AUD. We hypothesize that the combination of PTSD+AUD will exacerbate behavioral and molecular endpoints, functional assessments of excitatory/inhibitory neurotransmitter and receptor levels, dendritic morphology, neuronal plasticity and striatal activation compared to either condition alone and that these deficits will be reversed by neurotherapeutic intervention. We will test this hypothesis using the following Specific Aims: 1) Evaluate the influence of comorbid PTSD+AUD on striatal-dependent behaviors [including alcohol drinking, habit behavior and anxiety], neurite morphology, markers of excitatory/inhibitory neurotransmission, [and components of the cannabinoid system] compared to either condition alone, 2) Quantify the long-term impacts of comorbid PTSD+AUD on striatal neurotransmitter levels (neurochemical) and neuroactivation (functional) using novel magnetic resonance imaging techniques in a longitudinal manner in vivo compared to either condition alone. [In both of these aims we will evaluate the ability of a cannabinoid-based neurotherapeutic treatment to improve/restore cellular and molecular deficits associated with PTSD+AUD and thereby, to improve striatal-based behaviors and function.]